(R)-Carnitine is a naturally occurring compound found in both plant and animal tissues. High concentrations are located in vertebrates' heart and muscle tissues, which depend heavily upon fatty acid oxidation as an energy source. Carnitine is a substrate of a class of enzymes, carnitine acyltransferases, that catalyze the reversible transfer of acyl groups between carnitine and acyl coenzyme A. Acylated carnitine acts as a carrier of fatty acyl groups across mitochondrial membranes in vectorial transport mediated by a translocase enzyme. Carnitine has proven useful in the treatment of myocardial ischemia in animals. It facilitates the transfer of fatty acids in damaged areas, hence increasing energy product and promoting survivability of the tissue. See Gandour, et al., Bioorganic Chem., 13, 197-208 (1985).
Hemiacetylcarnitinium (HAC) is a good inhibitor of carnitine acetyltransferase (CAT). This analog structurally resembles the hemicholiniums, which inhibit acetylcholine synthesis by blocking the uptake of choline and serve a substrates for choline acetyltransferase.
Hemipalmitoyl carnitinium (HPC) is a potent inhibitor of carnitine palmitoyltransferase (CPT), which is believed to be rate limiting for hepatic mitochondrial .beta.-oxidation of long-chain fatty acids. CP activity usually increases under certain conditions, e.g., starvation and diabetes, resulting in higher levels of fatty-acid oxidation and ketogenesis. CPT inhibitors (e.g., 2-tetradecylglycidyl-CoA and amino- and palmitoylaminocarnitine) decrease blood ketone and blood glucose concentrations in vivo, suggesting that CPT inhibitors can aid in alleviating the diabetic syndrome.
Effective CPT inhibitors have certain moieties in common. Most have a long-chain alkyl group attached to either CoA or a carnitine analog. Illustrative of these inhibitors are: 2-bromopalmitoyl-CoA and -carnitine S-2-bromomyristoylthiocarnitine, 2-alkyl-2-glycidylcarnitine and -CoA, (1-pyrenebutyryl)-carnitine and -CoA, S-heptadecyl-CoA and heptadecan-2-onyldethio-CoA, palmitoylaminocarnitine, and myristoylaminocarnitine. CPT recognizes molecules containing a long-chain alkyl and a trimethylammonium group (e.g., palmitoylcholine and N-hexadecylsulfobetaine). Aminocarnitine, also known as emeriamine, and methylglyoxal bis(guanylhydrazone) are the known small molecule inhibitors of CPT. Some of the above inhibitors, however, are only effective with certain preparations of CPT. Furthermore, the location of the binding site of malonyl-CoA, the physiological inhibitor of CPT, has not been conclusively demonstrated. In any case, HPC is the most potent synthetic reversible inhibitor of catalytic activity in purified CPT assayed to date. See Gandour, et al., Archives of Biochem. and Biophys., 267 (2), 515-520 (1988).
Accordingly, there is a need for more potent inhibitors of CPT.